Potentiation of a Topoisomerase I Inhibitor, Karenitecin, by the Histone Deacetylase Inhibitor Valproic Acid in Melanoma: Translational and Phase I/II Clinical Trial

Abstract

Purpose: The novel topoisomerase I inhibitor karenitecin (KTN) shows activity against melanoma.We examined whether histone deacetylase inhibition could potentiate the DNA strand cleavage, cytotoxicity as well as the clinical toxicity, and efficacy of KTN in melanoma. Experimental Design: Apoptosis, COMET, and xenograft experiments were carried out as described previously. A phase I/II trial of valproic acid (VPA) and KTN was conducted in patients with stage IV melanoma, with any number of prior therapies, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Results: VPA pretreatment potentiated KTN-induced apoptosis in multiple melanoma cell lines and in mouse A375 xenografts. VPA increased KTN-induced DNA strand breaks. In the phase I/II trial, 39 patients were entered, with 37 evaluable for toxicity and 33 evaluable for response. Somnolence was the dose-limiting toxicity.The maximum tolerated dose forVPA was 75 mg/kg/d; at maximum tolerated dose, serumVPA was f200 Ag/mL (1.28 mmol/L). At the dose expansion cohort, 47% (7 of 15) of patients had stable disease; median overall survival and time to progression were 32.8 and10.2 weeks, respectively. Histone hyperacetylation was observed in peripheral blood mononuclear cells at maximum tolerated dose. Conclusion: VPA potentiates KTN-induced DNA strand breaks and cytotoxicity. VPA can be combined at 75 mg/kg/d for 5 days with full-dose KTN without overlapping toxicities. In metastatic poor prognosis melanoma, this combination is associated with disease stabilization in 47% of patients. Further testing of this combination appears warranted.

Evaluation of melanogenesis in A-375 melanoma cells treated with 5,7-dimethoxycoumarin and valproic acid

“…A similar result was obtained in cultures simultaneously stimulated with 1 mM VPA and 0.5 M etoposide; therefore, VPA made M14 cells more sensitive to standard chemotherapy. This suggests that some of the HDACis may be useful in the combined therapy of malignant melanoma [42]. It is noteworthy that the results presented in Fig.…”

“…Many HDACis, among them VPA, are currently undergoing phase I or II clinical trials [11,41]. Daud et al [42] used VPA (30-90 mg/kg/24 h) and the topoisomerase I inhibitor Karenitecin (KNT at 0.8 and 1 mg/m 2 /24 h) and achieved stabilization of the disease in 13 out of 33 (39%) patients with the diagnosed melanoma. The phase I and II clinical trials conducted by Rocca et al [11] revealed that combined treatment with VPA, decarbazine and INF-γ did not give desirable effects.…”

Molecular Pathways: Old Drugs Define New Pathways: Non-Histone Acetylation at the Crossroads of the DNA Damage Response and Autophagy

“…VPA pretreatment has been shown to increase the cytotoxicity of the topoisomerase inhibitor karenitecin in melanoma cells and in animal xenografts (53). The VPA-karenitecin combination was clinically evaluated in patients with stage IV melanoma with encouraging results: 47% of the patients had stable disease with median progression-free survival of 10.3 weeks versus 34% with stable disease with median progression-free survival of 7.9 weeks in patients treated with single-agent karenitecin (53).…”

Preclinical Predictors of Anticancer Drug Efficacy: Critical Assessment with Emphasis on Whether Nanomolar Potency Should Be Required of Candidate Agents: TABLE 1

“…VPA possesses a high oral bioavailability and is well tolerated by patients. VPA at up to 75 to 120 mg/kg/day was well tolerated (Mü nster et al, 2007(Mü nster et al, , 2009Daud et al, 2009) …”